Bexotegrast in Patients with Idiopathic Pulmonary Fibrosis: The INTEGRIS-IPF Clinical Trial

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives: Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods: This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results: Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with www.clinicaltrials.gov (NCT04396756).

Keywords: IPF; efficacy; fibrotic disease; safety.

Figure 1.

Study design. *One participant, randomized to placebo, received 320 mg bexotegrast for approximately 1 week because of incorrect study-drug dispensation. No adverse events were reported for this participant. They are included in the denominator of the placebo and 320-mg bexotegrast group for the safety analyses. This figure represents the intent-to-treat population. Y/N = yes/no.

Figure 2.

Participant disposition. *Adverse event (n = 3), withdrawal of consent (n = 1), physician decision (n = 1). ^†Adverse event (n = 1), withdrawal of consent (n = 2), physician decision (n = 1). ^‡Eighty-eight participants were randomized to receive bexotegrast; however, one participant, randomized to placebo, received both placebo and 320 mg bexotegrast for approximately 1 week because of incorrect study-drug dispensation. They are included in the denominator of the placebo and 320-mg bexotegrast groups for the safety analyses.

Figure 3.

Change in FVC from baseline to Week 12 (efficacy for modified intent-to-treat population). (A–D) Change in FVC from baseline through Week 12 in all participants receiving (A) 40 mg, (B) 80 mg, (C) 160 mg, and (D) 320 mg bexotegrast compared with placebo. Change from baseline was analyzed using a mixed model for repeated measures. *P < 0.05 versus placebo. **P < 0.01 versus placebo. LS = least squares.

Figure 4.

Percentage of participants with FVC (A) relative decline ⩾10% of predicted and (B) absolute decline ⩾10% of predicted at Week 12 (efficacy for modified intent-to-treat population).

Figure 5.

Exploratory endpoints. (A) Mean change in QLF (%) from baseline to Week 12. (B) Least squares (LS) mean change from baseline in plasma ITGB6 relative to placebo at Weeks 4 and 12. (C) LS mean change from baseline in serum PRO-C3 relative to placebo at Weeks 4 and 12. The data in (A) are per computed tomography protocol population (a subset of the intent-to-treat population with available high-resolution computer tomography imaging data and images) who completed the study without any major protocol violations within the prespecified time interval between screening and randomization. The data in (B) and (C) are from the pharmacodynamic analysis population. Change from baseline in biomarker concentration was analyzed using a mixed model for repeated measures. *P < 0.05 versus placebo. **P < 0.01 versus placebo. ****P < 0.0001 versus placebo. ITGB6 = integrin β-6; NPX = Normalized Protein eXpression; PRO-C3 = type III collagen synthesis neoepitope; QLF = quantitative lung fibrosis.